TNF is a protein produced by macrophages and mononuclear phagocytes upon activation by endotoxin or other microbial products or stimuli [E. A. Carswell et al., "An Endotoxin-Induced Serum Factor That Causes Necrosis Of Tumors", Proc. Natl. Acad. Sci. USA, 72, pp. 3666-70 (1975); P. J. Hotez et al., "Lipoprotein Lipase Suppression In 3T3-L1 Cells By A Haematoprotozoan-Induced Mediator From Peritoneal Exudate Cells", Parasite Immunol., 6, pp. 203-09 (1984)]. Although TNF is cytotoxic or cytostatic for a broad range of animal and human cancer cells in vitro and induces hemorrhagic necrosis in certain animal tumors and heterotransplanted human tumors in vivo, it exerts little or no cytotoxicity on normal cells [K. Haranaka and N. Satomi, "Note: Cytotoxic Activity Of Tumor Necrosis Factor (TNF) On Human Cancer Cells In Vitro", Japan J. Exp. Med., 51, pp. 191-94 (1981); L. Old, "Cancer Immunology: The Search For Specificity - G.H.A. Clowes Memorial Lecture", Cancer Research, 41, pp. 361-75 (1981); B. D. Williamson et al., Proc. Natl. Acad. Sci. USA, 80, pp. 5397-401 (1983)].
Malignant diseases are a group of diseases characterized by tumorigenic or neoplastic cell growth. Such diseases include malignant hematological systemic diseases, carcinomas, sarcomas, myelomas, melanomas, lymphomas and papillomas. Non-malignant neoplastic diseases, including non-malignant tumors, are also characterized by neoplastic cell growth which is localized to a specific area. The transformation of normal cells within the body into either malignant or non-malignant neoplasms may be induced by chemical carcinogens, radiation, physical agents or spontaneous tumorigenic growth.
The precise etiology of many malignant and non-malignant diseases remains unknown. Accordingly, treatments for these diseases are limited, and effective agents are not always conventionally available for a specific disease. Such diseases have been treated, for example, by surgical techniques or by non-surgical methods including chemotherapy, radiation and immunotherapy. Any value of such treatment techniques, however, is often diminished by adverse side effects or risks attendant with their use. For example, non-surgical techniques such as chemotherapy generally have immunosuppressant effects and may increase the patient's susceptibility to secondary infections. Surgical treatments to excise malignant or non-malignant tumors involve risks which accompany any invasive procedure and may not effectively remove or eliminate the entire transformed cell population. Moreover, certain malignant diseases are resistant to conventional treatment techniques. For example, most skin melanomas are considered to be radio-resistant. No single agent or combination chemotherapy has been successful in effecting consistent regressions of malignant melanomas. Malignant renal cell carcinoma is also resistant to available single agent and combination chemotherapies.
Alternative methods of treatment for malignant and non-malignant diseases have involved the use of monoclonal antibodies to tumor-specific antigens on the surface of transformed cells. The effectiveness of such treatments, typically involving murine monoclonal antibodies, is often limited by a variety of factors, including anti-antibody responses which impede the effectiveness of further administrations of the murine antibody [G. E. Goodman et al., "Pilot Trial Of Murine Monoclonal Antibodies In Patients With Advanced Melanoma", J. Clin. Oncol., 3, pp. 340-51 (1985)]. Other reported side effects of monoclonal antibody treatments include anaphylaxis, fever and chills.
In view of the disadvantages of such therapies, various treatments have been directed to augmenting the body's immune response to tumorigenic cells by increasing the body's level of certain lymphokines. For example, TNF alone is known to inhibit the growth of or to kill tumor cells. In addition, combinations of human lymphotoxin and human gamma interferon have been reported to inhibit tumor growth [European patent application 128,009]. Combinations of TNF and human interferon have also been reported to demonstrate a greater growth inhibitory or cytotoxic effect on human tumors than the sum of their separate effects [L. Fransen et al., "Recombinant Tumor Necrosis Factor: Its Effect And Its Synergism With Interferon-.gamma. On A Variety Of Normal And Transformed Human And Mouse Cell Lines", Eur. J. Cancer Clin. Oncol., 22, pp. 419-26 (1986); B. D. Williamson et al., "Human Tumor Necrosis Factor Produced By Human B-Cell Lines: Synergistic Cytotoxic Interaction With Human Interferon", Proc. Natl. Acad. Sci. USA, 80, pp. 5397-401 (1983); see also European patent application 131,789]. Although TNF has shown promise as a potent cytotoxic agent, its usefulness as a therapeutic for treating malignant and non-malignant diseases has been restricted by dose-limiting toxic side effects.
TNF has been suggested as one of the mediators in the pathogenesis of endotoxic shock [B. Beutler et al., "Passive Immunization Against Cachectin/Tumor Necrosis Factor Protects Mice From Lethal Effect Of Endotoxin", Science, 229, pp. 869-71 (1985); B. Beutler and A. C. Cerami, "Cachectin And Tumor Necrosis Factor As Two Sides Of The Same Biological Coin", Nature, 320, pp. 584-88 (1986)]. In addition to its contribution to such systemic effects, TNF can play a role in local inflammation as in osteoarthritis [J. M. Dayer et al., "Cachectin/ Tumor Necrosis Factor Stimulates Collagenase And Prostaglandin E.sub.2 Production By Human Synovial Cells And Dermal Fibroblasts", J. Exp. Med., 162, pp. 2163-68 (1985)].
The role of TNF in such pathogeneses may be attributable to its stimulation of prostaglandin or thromboxane production. Although there is no clear explanation of the pathogenic mechanisms in toxic shock, substantial increases in circulating prostaglandins have also been reported in a variety of experimental models for hemorrhagic and endotoxic shock and the thromboxane PGI.sub.2, as well as the prostaglandin PGE.sub.2, have been proposed as important mediators in the development of irreversible shock [J. R. Fletcher, in Biological Protection With Prostaglandins, I, pp. 65-72 (1985); R. R. Butler et al., "Elevated Plasma Levels Of Thromboxane (Tx) and Prostacyclin (PGI.sub.2) In Septic Shock", Circ. Shock, 8, pp. 213-14 (1981); R. H. Demling et al., Am. J. Physiol., 240, pp. H348-53 (1981); W. C. Wise et al., "Implications For Thromboxane A.sub.2 In The Pathogenesis Of Endotoxic Shock", Adv. Shock Res., 6, p. 83 (1981); H. Bult et al., "Blood Levels Of 6-Keto-PGF.sub.1.alpha., The Stable Metabolite Of Prostacyclin During Endotoxin-Induced Hypotension", Arch. Int. Pharmacodyn, 236, pp. 285-86 (1978); J. A. Cook et al., "Elevated Thromboxane Levels In The Rat During Endotoxic Shock", J. Clin. Invest., 65, pp. 227-30 (1980)]. Although it has been reported that non-steroidal anti-inflammatory drugs appear to protect against certain lethal effects of endotoxin in experimental animals, such agents have not been used clinically to treat human patients in endotoxic and hemorrhagic shock [B. L. Short et al., "Indomethacin Improves Survival In Gram-Negative Sepsis", Adv. Shock Res., 6, pp. 27-36 (1981); P. M. Almqvist et al., "Treatment Of Experimental Canine Endotoxin Shock With Ibuprofen, A Cyclooxygenase Inhibitor", Circ. Shock, 131, pp. 227-32 (1984); E. R. Jacobs, J. Clin. Invest., 70, pp. 536-41 (1982) P. V. Halushka et al., "Protective Effects Of Aspirin In Endotoxic Shock," J. Pharmacol. Exp. Therm., 218, pp. 464-69 (1981)].
To date, therefore, conventional methods and therapeutic agents have not proved to be effective in the treatment of many malignant and non-malignant diseases. Accordingly, the need exists for therapeutic agents and methods which avoid the disadvantages of these conventional agents and methods while providing effective treatment for these diseases.